Breast Cancer and HER2

HER2 (human epidermal growth factor receptor 2) is a transmembrane tyrosine kinase receptor and a member of the ErbB protein family (ie, the epidermal growth factor receptor [EGFR] family). It is sometimes also known as NEU. HER2 gene product is overexpressed in 18-20% of invasive breast cancers. ^[1]  Activation of this class of cellular receptors is known to result in increased activity of a variety of molecular pathways associated with tumor growth and progression.

Testing for HER2

The American Society of Clinical Oncology and the College of American Pathologists has issued the following updated recommendations for HER2 testing in breast cancer ^{[2, 3]} :

• HER2 status should be determined in all patients with invasive breast cancer on the basis of 1 or more test results.

• Testing must be performed in an accredited laboratory. Laboratories should be able to show high concordance with a validated HER2 test on a large and representative set of specimens.

• HER2-positive status is indicated by evidence of protein overexpression or gene amplification.

• When results are equivocal, reflex testing should be performed with an alternative assay, and repeat testing should be considered if results are discordant with other findings.

• Providers should recommend HER2-targeted therapies if the patient's HER2 test result is positive and such treatment is clinically appropriate. Most experts do not recommend HER2-targeted therapy if the HER2 test result is negative and there is no histopathologic discordance with HER2 testing. Delay the decision to recommend HER2-targeted therapy if the HER2 test result is equivocal. Reflex testing should be done on the same specimen.

These recommendations have also been adapted and studied in other countries, such as the United Kingdom, France, and Italy. ^{[4, 5, 6]}

Testing for HER2 may be done by means of either immunohistochemistry (IHC) or in situ hybridization (ISH). The scoring method for HER2 expression on IHC is based on the cell membrane staining pattern and is as follows:

• 3+: Positive HER2 expression - Uniform intense membrane staining of more than 30% of invasive tumor cells.

• 2+: Equivocal for HER2 protein expression - Complete membrane staining that is either nonuniform or weak in intensity but has circumferential distribution in at least 10% of cells.

• 0 or 1+: Negative for HER2 protein expression.

• HER2 test results must be reported as indeterminate if technical issues prevent one or both tests from being interpreted accurately.

ISH has been used to establish HER2 status when IHC yields equivocal results, but it is now also being used alone for this purpose in an increasing number of centers. The interpretation for dual-probe HER2 ISH testing (HER2-to–chromosome enumeration probe 17 [CEP17[) ratio and gene copy number) is as follows:

• Possible positive result: HER2/CEP17 ratio ≥2.0 or HER2 copy number ≥6 

• Possible equivocal result: HER2/CEP17 ratio < 2.0 and  HER2 copy number ≥4 but < 6  (requires performing alternative ISH test to confirm equivocal result or IHC if not previously performed)

• Possible negative result: HER2/CEP17) ratio < 2.0  and   HER2 copy number < 4

Treatment of HER2-positive breast cancer

Before the advent of HER2-targeted therapy, HER2 overexpression was associated with a worse prognosis (higher rate of recurrence and mortality), independent of other clinical features (eg, age, stage, tumor grade), especially in patients who did not receive adjuvant chemotherapy. HER2-targeted therapy, starting with the monoclonal antibody trastuzumab, in combination with chemotherapy and endocrine therapy, has significantly improved response rates and survival. Additional HER2-targeted agents have included other monoclonal antibodies (eg, pertuzumab), tyrosine kinase inhibitors (eg, neratinib, tucatinib), and antibody-drug conjugates (eg, ado-trastuzumab emtansine, trastuzumab deruxtecan).

Since 2017, the US Food and Drug Administration (FDA) has approved 4 biosimilars of trastuzumab (Herzuma, Ogivri, Ontruzant, Trazimera)  to treat HER2-overexpressed breast cancer. All biosimilars of trastuzumab have demonstrated efficacies and safety outcomes similar to those of the standard trastuzumab. ^{[7, 8, 9, 10]}

Trastuzumab is administered intraveneously. In 2019, the FDA approved a formulation for subcutaneous (SC) administration, trastuzumab/hyaluronidase (Herceptin Hylecta), which contains trastuzumab in combination with recombinant human hyaluronidase PH20, an enzyme that increases the permeability of subcutaneous tisses. Trastuzumab/hyaluronidase is given as a slow SC administration over 2-5 minutes instead of a 30-90 minute IV infusion. It is approved for use in combination with chemotherapy for the treatment of select patients with HER2-positive early breast cancer, in combination with paclitaxel in patients with metastatic HER2-positive breast cancer as a frontline treatment, and alone for patients with metastatic disease who had received at least 1 prior chemotherapy regimen. ^{[11, 12, 13]}

In June 2020, the FDA granted accelerated approval to a new fixed-dose combination of pertuzumab/trastuzumab/hyaluronidase (Phesgo) for SC use in combination with IV chemotherapy for the treatment of early and metastatic HER2-positive breast cancer. SC administration allows patients to receive treatment either at a treatment center or at home by a healthcare professional..  ^[14]

Go to Breast Cancer for complete information on this topic.

Although several methods for HER2 testing have been developed, approximately 20% of current HER2 testing may be inaccurate. Therefore, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) have recommended guidelines in HER2 testing to ensure accuracy. ^{[2, 3]}

Breast cancer specimens should initially undergo HER2 testing by a validated immunohistochemistry (IHC) assay (ie, HercepTest, Dako, Glostrup, Denmark) for HER2 protein expression. ^[15] The scoring method for HER2 expression is based on the cell membrane staining pattern and is as follows:

• 3+: Positive HER2 expression - Uniform intense membrane staining of more than 30% of invasive tumor cells.
• 2+: Equivocal for HER2 protein expression - Weak to moderate complete membrane staining observed in > 10% of tumor cells.
• 0 or 1+: Negative for HER2 protein expression.

Breast cancer specimens with equivocal IHC should undergo validation using a HER2 gene amplification method, such as in situ hybridization (ISH). More centers are relying on FISH alone for determining HER2 status.

In general, ISH testing is thought to be more reliable than IHC, but it is more expensive. Equivocal IHC results can be seen in 15% of invasive breast cancers, whereas equivocal HER2 ISH results are seen in less than 3% of invasive breast cancer specimens and those that had previously been considered HER2 positive. Discordant results (IHC 3+/ISH negative or IHC less than 3+/ISH positive) have been observed in approximately 4% of specimens. Currently, no data support excluding this group from treatment with trastuzumab.

The interpretation for HER2 ISH testing (HER2/chromosome enumeration probe 17 [CEP17] ratio and gene copy number) is given below:

• Possible positive result: HER2/CEP17 ratio ≥2.0 or  HER2 copy number ≥6 

• Possible equivocal result: HER2/CEP17 ratio < 2.0 and  HER2 copy number ≥4 but < 6  (requires performing alternative ISH test to confirm equivocal result or IHC if not previously performed)

• Possible negative result: HER2/CEP17) ratio < 2.0  and   HER2 copy number < 4

Overexpression of HER2 occurs in approximately 20% of breast cancers and correlates with a more aggressive phenotype. Prognosis for patients with HER2-positive breast cancer was worse before the development of HER2-targeted therapies. The advent of trastuzumab, a monoclonal antibody (mAb) targeting the extracellular domain of the receptor, changed the treatment paradigm for HER2-positive breast cancer. Trastuzumab has a powerful synergism with a variety of chemotherapeutics, yet lacks their adverse effects (with the notable exception of cardiotoxicity, which means it generally should not be given with anthracyclines).

Several studies (HERA, FinHer, NSABP B-31, BCIRG006, N9831) demonstrated that the inclusion of trastuzumab produces roughly a 50% improvement in disease-free survival and 33% improvement in overall survival, regardless of the chemotherapy regimen or sequence of trastuzumab delivery. These trials randomized 11,650 women with early-stage HER2-positive breast cancer to trastuzumab versus non-trastuzumab-based adjuvant chemotherapy, and based on their results, trastuzumab was approved by the US Food and Drug Administration (FDA) for the treatment of HER2-positive disease in the adjuvant setting. 

Another study from the BCIRG006 further established that adjuvant trastuzumab for 1 year improved disease-free and overall survival among women with early-stage HER2-positive breast cancer at 5 years. ^[16] On the basis of those early trials, 12 months of trastuzumab has been the standard duration. Subsequent studies on shorter durations of therapy have yielded conflicting results, but a meta-analysis concluded that a shorter duration of adjuvant trastuzumab therapy (eg, 6 months, as in the PERSEPHONE trial) produces disease-free survival that is noninferior to that of 12 months of treatment, and is associated with lower rates of cardiac toxic effects. These authors suggest that "a shorter duration of adjuvant trastuzumab may be the preferred option for patients with low-risk disease or a predisposition to cardiac toxic effects." ^[17]

Trastuzumab has been studied in combination with various agents. In BCIRG006, a nonanthracycline regimen plus trastuzumab had a more favorable risk-benefit ratio than anthracycline-based regimens, due to similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. ^[16]  However, in the phase III ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Options) trial, disease-free survival was not significantly longer with lapatinib plus trastuzumab, compared with trastuzumab alone, and toxicity was greater. ^[18]

In contrast, results of the Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial suggested that the combination of lapatinib and trastuzumab may be valid for neoadjuvant treatment of HER2-positive breast cancer. The pathologic complete response rate (pCR) rate was significantly higher in the group given lapatinib and trastuzumab than in the group given trastuzumab alone (51.3% versus 29.5%; P=0.0001). ^[19]

In 2019, the FDA approved ado-trastuzumab emtansine (Kadcyla; T-DM1), which contains trastuzumab covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative), for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane- and trastuzumab-based treatment. Approval was based on KATHERINE, a randomized, multicenter, open-label clinical trial in which T-DM1 reduced the risk of an invasive recurrence or death by 50% compared with trastuzumab. The rate of invasive disease or death was 12.2% in patients in the T-DM1 arm, compared with 22% in the trastuzumab arm. Secondary endpoints of disease-free survival and distant recurrence–free survival interval also showed clinically meaningful improvements with T-DM1 relative to trastuzumab. ^[20]

Neratinib is an irreversible tyrosine kinase inhibitor of EGFR, HER1, HER2, and HER4. Dual blockade by antiangiogenic/HER2 agents (eg, neratinib) targeting HER and EGFR pathways produces greater inhibition of human breast cancer cell lines. In July 2017, the FDA approved neratinib for extended adjuvant therapy for early stage HER2 positive breast cancer following adjuvant trastuzumab-based therapy. ^[21]  The approval was based on the the phase 3 ExteNET trial, a multicenter, randomized, double-blind, placebo-controlled trial of neratinib following adjuvant trastuzumab treatment. After 2 years of follow-up, invasive disease-free survival (iDFS) was 94.2% in patients treated with neratinib, compared with 91.9% in those receiving placebo. ^[22]

Pertuzumab (Perjeta) is a humanized monoclonal antibody that blocks the activation of the HER2 receptor by hindering dimerization; it elicits action at a different ligand binding site from trastuzumab. The FDA approved pertuzumab for neoadjuvant treatment in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive). Approval was based on a randomized trial in which 39.3% of patients treated with pertuzumab, trastuzumab, and docetaxel achieved a pathologic complete response (pCR), compared with 21.5% of patients treated with trastuzumab and docetaxel. ^[23]  

Pertuzumab, in combination with trastuzumab and chemotherapy, is also approved for adjuvant treatment of HER2-positive early breast cancer at high risk of recurrence. Approval for this indication was based on the findings from the APHINITY trial,a multicenter, double-blind, placebo-controlled study in 4804 patients. At a median follow-up of 45.4 months, 7.1% patients in the pertuzumab group had developed invasive breast cancer, compared to 8.7% patients in the placebo group. At 3 years, an estimated 94.1% of patients in the pertuzumab group were free of invasive breast cancer, compared to 93.2% of patients in the placebo group. ^[24]

Endocrine therapy

Approximately 50% of HER2-positive breast cancers express hormone receptors (HRs). Adjuvant endocrine therapy in HER2-positive, HR-positive early-stage breast cancer patients may comprise tamoxifen or aromatase inhibitors (ie, anastrozole, exemestane, letrozole). A systematic review and meta-analysis of six randomized, controlled trials that included 5390 patients with HER2-positive breast cancer found no difference in disease-free survival between tamoxifen and aromatase inhibitors. In view of their similar efficacy, the agents' different adverse effect profile can help guide treatment selection: thrombosis or embolism occurs more often with tamoxifen, while musculoskeletal symptoms, osteoporosis, and vaginal dryness occur more often with aromatase inhibitors. ^[25]   

In the metastatic setting, a pivotal phase III trial compared first-line chemotherapy (doxorubicin/epirubicin and cyclophosphamide or paclitaxel) plus trastuzumab versus chemotherapy alone in HER2-positive patients. Trastuzumab plus chemotherapy was associated with a significant improvement in time to disease progression (7.4 mo vs 4.6 mo), objective response rate (50% vs 32%), and 1-year survival (25.1 mo vs 20.3 mo) compared with chemotherapy alone. ^[26]

Additionally, evidence suggested that in women with advanced HER2-positive breast cancer, survival is better with up-front use of trastuzumab plus chemotherapy than it is with sequential administration (ie, with trastuzumab reserved for the time of disease progression on an initial chemotherapy regimen). Based on those results, the FDA approved trastuzumab for first-line therapy in HER2-positive metastatic breast cancer. 

Results from the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab, and a taxane as the standard of care for first-line therapy of HER2-positive metastatic breast cancer. ^[27] In CLEOPATRA, the addition of pertuzumab to trastuzumab and docetaxel resulted in a median progression-free survival (PFS) of 18.5 months—6.1 months longer than with trastuzumab and docetaxel—with minimal to no increase in cardiac toxic effects. ^[28]  On the basis of those results, the FDA approved pertuzumab, in combination with trastuzumab and docetaxel, for the treatment of HER2-positive metastatic breast cancer in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.  

End-of-study analysis of CLEOPATRA demonstrated that improvements in overall survival with pertuzumab, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles were also maintained. ^[29]

Another agent used in the treatment of HER2-positive metastatic breast cancer is lapatinib, a tyrosine kinase inhibitor (TKI). Lapatinib was approved in 2007 for the treatment of metastatic breast cancer in HER2-positive patients after progression on trastuzumab. This small molecule is known to block multiple epidermal growth factor receptors (EGFRs), EGFR (HER1) and HER2, and is generally well tolerated, with the main toxicities being diarrhea, skin rash, fatigue, and nausea.

An analysis of cardiac toxicity found that 1.6% of patients exposed to lapatinib experienced a decline in left ventricular ejection fraction (LVEF), with 0.2% being symptomatic, lower than the comparable incidence observed with trastuzumab. ^[30]  Preclinical data indicated synergistic activity between lapatinib and trastuzumab, leading to a randomized study of this combination.

A phase III trial involving 296 heavily pretreated, trastuzumab-refractory metastatic breast cancer patients randomized to treatment with lapatinib alone or lapatinib with trastuzumab reported combination therapy significantly improved PFS (8.4 wks vs 12 wks) compared with lapatinib alone. ^[31]  There was a nonsignificant trend toward improved median overall survival. Diarrhea and rash were the most common adverse effects. An asymptomatic decline in LVEF was seen in 5% of patients in the combination arm, compared with 2% in the lapatinib-alone arm.

In the phase III EMILIA trial, 991 patients with HER2-positive advanced breast cancer previously treated with trastuzumab and taxane were randomized to treatment with the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) or lapatinib plus capecitabine. T-DM1 was shown to significantly prolong PFS (9.6 months vs. 6.4 months) and overall survival (30.9 months vs. 25.1 months) compared with lapatinib plus capecitabine, and was associated with a better toxicity profile. ^[24] On the basis of the results of EMILIA, the FDA approved T-DM1 for treatment of metastatic HER2-positive breast cancer.

Final overall analysis of survival in EMILIA, which included patients who crossed over from control to T-DM1, confirmed that median overall survival was longer with T-DM1 than with control (29.9 vs 25.9 months, respectively; hazard ratio [HR] 0.75). ^[32]  T-DM1 has become established as standard second-line therapy for metastatic HER2-positive breast cancer. ^[27]

Trastuzumab deruxtecan is an antibody-drug conjugate that contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the topoisomerase I inhibitor, deruxtecan. In the open-label, phase II DESTINY-Breast01 study (n = 184), patients who had received a median of 6 previous treatments were given trastuzumab deruxtecan every 3 weeks. The overall response rate was 60.3%, complete responses were observed in 4.3%, and partial responses in 56%. Median duration of response was 14.8 months. Median PFS was 16 months. ^[33]  On the basis of that study, the FDA approved trastuzumab deruxtecan for treatment in patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. ^[34]

In the DESTINY-Breast03 trial, which compared trastuzumab deruxtecan with T-DM1 in patients with unresectable or metastatic HER2+ breast cancer who had been previously treated with trastuzumab and a taxane in the advanced/metastatic setting, the 12-month PFS rate was 75.8%, vs 34.1% with T-DM1 (HR, 0.28). The median PFS was not reached for trastuzumab deruxtecan; it was 6.8 months for T-DM1. However, serious drug-related adverse events occurred in 10.9% of patients taking trastuzumab deruxtecan, vs 6.1% of patients taking T-DM1. ^[27]

In 2020, tucatinib was approved by the FDA. It is an orally bioavailable, small molecule tyrosine kinase inhibitor (TKI) that is highly selective for HER2. This drug is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

Approval was based on the HER2CLIMB trial (n=612), an international multicenter study that randomized heavily pretreated patients to receive trastuzumab and capecitabine plus either tucatinib or placebo. The median PFS in the tucatinib-treated group was 7.8 months, compared with 5.6 months in the control arm. The median overall survival in the tucatinib-treated arm was 21.9 months, versus 17.4 months in the control arm. The median PFS for patients with baseline brain metastases in the tucatinib-treated arm was 7.6 months, compared with 5.4 months for patients in the control arm. ^[35]

See Breast Cancer Treatment Protocols for summarized information.